ETIOLOGY OF TREATMENT-INDUCED SECONDARY LEUKEMIA

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We propose to continue and expand our studies on the etiology of treatment- related acute nonlymphocytic leukemia (t-ANLL). Additional support is requested for two continuing and one new project. We have found that individuals being treated for Hodgkin;s disease (HD) and non-Hodgkin's lymphoma (NHL) as well as individuals with t-ANLL have low alkylguanine methyltransferase (AGT) activity as compared with healthy controls or individuals with ANLL de novo. We propose to test the hypothesis that low AGT activity is related to the development of t-ANLL. We will test AGT levels in patients undergoing radiation therapy for HD as controls and will follow AGT activity in individuals receiving high-dose chemotherapy with BCNU. We plan to develop an antibody to AGT to study the heterogeneity of this protein in lymphoid cells. Studies on mutability using both a chromosomal gene and an Epstein-Barr virus (EBV)-based plasmid will be carried out in a series of isogenic lymphoblastoid lines of differing AGT content to determine the relationship between activity and mutability after treatment with MNNG and BCNU. Chromosome breakage measured cytologically and biochemically will be correlated with AGT activity to test the hypothesis that low levels of AGT lead to higher mutability. In a new program, we propose to identify and isolate the putative genes located on chromosome 5. whose altered function as a result of recessive mutations (e.g., chromosome deletions, point mutations, and submicroscopic deletions of the type studied in the first programs) plays a role in the pathogenesis of ANLL. To accomplish this aim, the investigators will develop a physical linkage map of genes and anonymous sequences in the critical region of 5q; this map will be used to examine the DNA derived from leukemia cell of patients with deletions of 5q in order to identify submicroscopic deletions or other DNA rearrangements in the "normal" chromosome 5 homologue thereby identifying candidate genes for homozygous inactivation. These studies added to the continuing work of the Program will provide more definitive understanding of the etiology of t-ANLL.